Prescot Street, Liverpool, Merseyside L7 8XP, UK. Street, Liverpool, Merseyside L7 8XP, UK

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1 Journal of Medical Microbiology (2009), 58, DOI /jmm Case Report Correspondence Andrew Kirby In vivo development of heterogeneous glycopeptide-intermediate Staphylococcus aureus (hgisa), GISA and daptomycin resistance in a patient with meticillin-resistant S. aureus endocarditis Andrew Kirby, 1,2 Kavya Mohandas, 1 Caroline Broughton, 2 Timothy J. Neal, 1 Godfrey W. Smith, 1 Pearl Pai 3 and Carlos Nistal de Paz 1 1 Department of Medical Microbiology, Royal Liverpool & Broadgreen University Hospital Trust, Prescot Street, Liverpool, Merseyside L7 8XP, UK 2 Department of Infection & Host Defence, Liverpool University, 8th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK 3 Department of Nephrology, Royal Liverpool & Broadgreen University Hospital Trust, Prescot Street, Liverpool, Merseyside L7 8XP, UK Received 10 September 2008 Accepted 12 November 2008 We report a patient who developed a meticillin-resistant Staphylococcus aureus (MRSA) central venous catheter infection complicated by infective endocarditis. The patient was initially treated with glycopeptides, which led to the development of heterogeneous glycopeptide resistance, the detection of which required the use of a macro Etest screening test. Subsequently, the causative strain, confirmed by PFGE as a UK epidemic MRSA-15, was treated with daptomycin, and again resistance developed in vivo. The development in vivo of resistance to both these agents suggests that the resistance mechanisms may be associated. We suggest that the clinician managing MRSA infection should anticipate daptomycin resistance when reduced glycopeptide susceptibility is detected. Case report A 41-year-old male with worsening renal function of unknown aetiology was admitted to the Royal Liverpool University Hospital. A Tesio catheter (double lumen and tunnelled) was inserted in the internal jugular vein for dialysis. A week later, pus was noted at the exit site of the Tesio from which meticillin-resistant Staphylococcus aureus (MRSA) was isolated and for which intravenous (i.v.) vancomycin was given. The infection appeared to resolve and the catheter remained in situ. The following month, on 26 March 2005, he was readmitted with rigors, an inflamed exit site and temporary visual loss. MRSA was isolated from blood cultures taken through the catheter. This and subsequent isolates were speciated using standard methods. Antimicrobial susceptibilities were completed using the British Society for Antimicrobial Chemotherapy (BSAC) disc diffusion method (BSAC, 2007). This isolate was sensitive to Abbreviations: BSAC, British Society for Antimicrobial Chemotherapy; hgisa, heterogeneous glycopeptide-intermediate Staphylococcus aureus; i.v., intravenous; MRSA, meticillin-resistant S. aureus; TOE, transoesophageal echocardiograph; TTE, transthoracic echocardiogram. rifampicin, fusidic acid, trimethoprim, linezolid and gentamicin and resistant to clindamycin, ciprofloxacin and meticillin. Despite a diagnosis of endocarditis, a transthoracic echocardiogram (TTE) was not performed. The Tesio catheter was removed and the patient was started on i.v. teicoplanin (until 10 May) and fusidic acid (doses and duration unknown where not stated). No MRSA was isolated from 30 MRSA screens (nose, throat, axilla and groin) taken from this point onwards. On 1 July 2005, MRSA was isolated from blood cultures. Treatment was commenced with i.v. vancomycin and oral rifampicin. Glycopeptide susceptibility results for this and subsequent isolates are shown in Table 1. Due to difficulty in establishing i.v. access, his Tesio catheter (inserted June 2005) was not removed. Instead, vancomycin lock therapy of the catheter lumen was started in addition to i.v. therapy. After 4 weeks, MRSA was again isolated from blood cultures. A TTE demonstrated no cardiac vegetations and a transoesophageal echocardiograph (TOE) was declined by the patient. i.v. teicoplanin was given for 6 weeks with trough antibiotic levels maintained at mg l 21. Oral fusidic acid was also given for the first 4 weeks and the catheter was removed. Peritoneal dialysis G 2009 SGM Printed in Great Britain

2 Glycopeptide and daptomycin failure in MRSA infection Table 1. MICs (mg l 1 ) of the MRSA isolates (completed in duplicate and retrospectively) from the patient For comparison, BSAC (2007) MIC breakpoints (mg l 21 ) for staphylococcal spp. are as follows. Teicoplanin:.8 resistant, 8 intermediate, 4 sensitive; vancomycin:.8 resistant, 8 intermediate, 4 sensitive; daptomycin:.1 resistant, 1 sensitive; linezolid:.4 resistant, 4 sensitive. Results in italics prospectively reported by the Antibiotic Resistance Monitoring & Reference Laboratory (ARMRL) for England and Wales, Colindale. Isolate Teicoplanin Teicoplanin macro Etest Vancomycin Vancomycin macro Etest Daptomycin Linezolid March July December May May December was attempted but failed, leading to arterio-venous fistula dialysis by October. The patient was well until December 2005, when MRSA was again isolated in blood cultures. This isolate was screened for heterogeneous glycopeptide-intermediate S. aureus (hgisa) resistance, a form of glycopeptide intermediate resistance. Here a subpopulation of a strain demonstrates reduced susceptibility to glycopeptides. The screening was completed using a macro Etest method [2 McFarland inoculum, 48 h incubation on brain heart infusion agar (Becton Dickinson) at 35 uc] which identifies the resistant subpopulation. A teicoplanin MIC of 12 mg l 21 by this method provides evidence of hgisa (Voss et al., 2007). This was obtained at the time of testing though in our retrospective assessment a macro Etest MIC of only 6mgl 21 was found (Table 2). [Changes in MICs for hgisa isolates have been reported elsewhere (Boyle-Vavra et al., 2000).] The isolate was confirmed as hgisa by population analysis profile area underneath the curve analysis (PAP AUC). PAP AUC is the gold standard for detecting hgisa. Here the AUC of the test S. aureus is divided by the corresponding AUC for Mu 3 (Wootten et al., 2001), an hgisa type strain. A ratio of 0.9 is consistent with hgisa. Our isolate had a PAP AUC ratio of Following this, oral linezolid at 600 mg b.d. was commenced. The source of infection was not identified despite investigation including a TOE. On 26 January 2006, day 45 of linezolid treatment, blood cultures grew MRSA sensitive to linezolid. Linezolid treatment was continued with the addition of gentamicin for 3 weeks (this isolate was fusidic acid-resistant; Table 2). A TOE performed in February 2006 showed two vegetations on the mitral valve. Antimicrobial therapy was changed to daptomycin 6 mg kg 21 every 48 h, oral rifampicin 600 mg b.d. and 80 mg i.v. gentamicin postdialysis for the first 2 weeks. In April, a repeat MRSA bacteraemia occurred. This isolate was still sensitive to daptomycin, leading to the addition of gentamicin. On 9 May 2006, the patient developed rigors and dysphasia. Blood cultures were positive for MRSA which was resistant to daptomycin by Etest MIC at 3 mg l 21 (all MIC values were derived using the Etest MIC method: 0.5 McFarland; Mueller Hinton agar for 24 h at 35 uc). A computerized tomography scan of the head revealed an infarct, a presumed embolus from his infected endocardial vegetations. With the failure of daptomycin and linezolid, a regime based on trimethoprim 200 mg b.d. and rifampicin 600 mg b.d. was started. In addition, despite the MIC for glycopeptides of the latest MRSA strain, now confirmed as GISA with an MIC of 8 mg l 21, with our experience of using high-dose teicoplanin, it was decided to administer teicoplanin with the aim of obtaining levels sufficient to negate the isolate s increased MICs. Hence, i.v. teicoplanin at 1.6 g daily for 1 week, then approximately every 48 h, Table 2. Antimicrobial susceptibilities of the patient s MRSA isolates according to BSAC methods S, Sensitive; R, resistant. Isolate Ciprofloxacin Gentamicin Erythromycin Fusidic acid Meticillin Mupiricin Rifampicin Tetracycline Trimethoprim March 05 R S R S R S S S S July 05 R S R S R S S S S December 05 R S R R R S S S S May 06 R S S S R S S S S May 06 R S S S R S S S S December 06 R S S S R S R S S 377

3 A. Kirby and others was prescribed, guided by levels. Throughout this period, teicoplanin pre-dose levels were always over 40 mg l 21 and often.80 mg l 21. i.v. gentamicin was also given for 2 weeks. Four weeks into treatment, a TTE showed no vegetations and mitral valve replacement was performed. Postoperatively, treatment with i.v. teicoplanin 1.6 g every 48 h, oral rifampicin 600 mg b.d. and oral trimethoprim 200 mg b.d. was continued until 18 September 2006, a total of 8 weeks. Isolates were available from March 2005 to May 2006, and PFGE was used to investigate their clonality (Harmony Method; Murchan et al., 2003). This demonstrated that the isolates were one clonal type by PFGE (Fig. 1). Comparison with NCTC strain 8325 and the molecular mass marker (data not shown) identified the strain as a UK epidemic MRSA-15, the most prevalent strain of MRSA in our institution. The patient remained asymptomatic for 6 months, when in December 2006 he presented again with rigors. Blood cultures were taken from which MRSA was isolated. A TOE showed no evidence of endocarditis but a radiolabelled Fig. 1. PFGE profiles of the MRSA isolates. Dates of isolates: A, 03/2005; B, 07/2005; C, 07/2005; D, 12/2005; E, 05/2006; F, 05/2006; G, 05/2006. white cell scan suggested osteomyelitis of the humerus, not at the site of the fistula. i.v. tigecycline (MIC mg l 21 ) was given for a period of 2 months and clindamycin for 1 month, the isolate testing sensitive to clindamycin. The patient responded both clinically and radiologically and has remained infection-free since. Fig. 2 gives an overview of this case history. Discussion The MRSA infection treated with glycopeptides in this report developed, in vivo, hgisa prior to developing GISA in response to this glycopeptide therapy. hgisa populations are those where approximately one subclone in every is able to grow in the presence of a higher concentration of a glycopeptide. The concern is that treatment will fail to eradicate the resistant subpopulation, which will fill the niche left by the killed susceptible population, leading to the clinical failure of glycopeptide therapy. The outcomes in hgisa infections were recently reviewed by Falagas et al. (2008). The evidence was inconclusive with a limited number of retrospective studies showing both adverse and no adverse outcomes. There is therefore still a need for prospective evaluation of outcomes in S. aureus-infected glycopeptide-treated patients. In view of the hgisa/gisa resistance, this patient was treated with daptomycin, which led to the development of daptomycin resistance in vivo. Sharma et al. (2008) also found that in patients with S. aureus infection, mainly endocarditis, treated with daptomycin, development of daptomycin resistance was not an uncommon finding. The mechanisms of hgisa, GISA and daptomycin resistance are still being investigated and may vary between strains. A proposed mechanism involves the upregulation of peptidoglycan synthesis leading to hgisa. In the presence of this upregulation, a further mutation allows significant cell wall thickening, causing a GISA phenotype (Neoh et al., 2008). The GISA phenotype, as we found, has been shown before to be associated with daptomycin resistance (Vikram et al., 2005; Hayden et al., 2005). It is suggested that daptomycin, the bactericidal effects of which are due to binding to the bacterial cell membrane, which causes an efflux of potassium ions from the cell and subsequent cell death (Silverman et al., 2003), is prevented from exerting its anti-staphylococcal action by the thickened cell wall (Jones et al., 2008). The thickened cell wall, with abundant daptomycin binding sites, sequesters and blocks daptomycin, preventing its action (Cui et al., 2003). In vitro studies have shown an association of reduced susceptibility to daptomycin with reduced susceptibility to glycopeptides (Sakoulas et al., 2006; Patel et al., 2006). Thus our case highlights that in patients with MRSA infection who demonstrate hgisa or GISA, which may require use of the macro Etest MIC for detection, clinicians 378 Journal of Medical Microbiology 58

4 Glycopeptide and daptomycin failure in MRSA infection Fig. 2. Schematic of significant clinical events, clinical management and in vitro susceptibility tests. CVC, central venous catheter; IE, infective endocarditis; vanc, vancomycin; rf, rifampicin; fd, fusidic acid; teic, teicoplanin; trim, trimethoprim; gent, gentamicin; MVR, mitral valve replacement. should expect daptomycin resistance to develop on daptomycin therapy. Acknowledgements The authors acknowledge the Antimicrobial Reference Laboratory, Southmead Hospital Bristol, and the Antibiotic Resistance Monitoring & Reference Laboratory (ARMRL) for England and Wales, Colindale. References Boyle-Vavra, S., Berke, S. K., Lee, J. C. & Daum, R. S. (2000). Reversion of the glycopeptide resistance phenotype in Staphylococcus aureus clinical isolates. Antimicrob Agents Chemother 44, British Society for Antimicrobial Chemotherapy (2007). Methods for Antimicrobial Susceptibility Testing, Version 7 ( uk/susceptibility_testing/bsac_standardized_disc_susceptibility_method. cfm). Cui, L., Ma, X., Sato, K., Okuma, K., Tenover, F. C., Mamizuka, E. M., Gemmell, C. G., Kim, M.-N., Ploy, M.-C. & other authors (2003). Cell wall thickening is a common feature of vancomycin resistance in Staphylococcus aureus. J Clin Microbiol 41, Falagas, M. E., Makris, G. C., Dimopoulos, G. & Matthaiou, D. K. (2008). Heteroresistance: a concern of increasing clinical significance? Clin Microbiol Infect 14, Hayden, M. K., Rezai, K., Hayes, R. A., Lolans, K., Quinn, J. P. & Weinstein, R. A. (2005). Development of daptomycin resistance in vivo in methicillin resistant Staphylococcus aureus. J Clin Microbiol 43, Jones, T., Yeaman, M. R., Sakoulas, G., Yang, S. J. & Proctor, R. A. (2008). Failures in clinical treatment of Staphylococcus aureus infection with daptomycin are associated with alterations in surface charge, membrane phospholipid asymmetry and drug binding. Antimicrob Agents Chemother 52, Murchan, S., Kaufmann, M. E., Deplano, A., de Ryck, R., Struelens, M., Zinn, C. E., Fussing, V., Salmenlinna, S., Vuopio- Varkila, J. & other authors (2003). Harmonization of pulsed-field gel electrophoresis protocols for epidemiological typing of strains of methicillin-resistant Staphylococcus aureus: a single approach developed by consensus in 10 European laboratories and its application for tracing the spread of related strains. J Clin Microbiol 41, Neoh, H. M., Cui, L., Yuzawa, H., Takeuchi, F., Matsuo, M. & Hiramatsu, K. (2008). Mutated response regulator grar is responsible for phenotypic conversion of Staphylococcus aureus from heterogeneous vancomycin-intermediate resistance to vancomycin-intermediate resistance. Antimicrob Agents Chemother 52, Patel, J. B., Jevitt, L. A., Hageman, J., McDonald, L. C. & Tenover, F. C. (2006). An association between reduced susceptibility to daptomycin and reduced susceptibility to vancomycin in Staphylococcus aureus. Clin Infect Dis 42, Sakoulas, G., Alder, J., Thauvin-Eliopoulos, C., Moellering, R. C. & Eliopoulos, G. M. (2006). Induction of daptomycin heterogeneous susceptibility in Staphylococcus aureus by exposure to vancomycin. Antimicrob Agents Chemother 50, Sharma, M., Riederer, K., Chase, P. & Khatib, R. (2008). High rate of decreasing daptomycin susceptibility during the treatment of persistent Staphylococcus aureus bacteraemia. Eur J Clin Microbiol Infect Dis 27, Silverman, J. A., Perlmutter, N. G. & Shapiro, H. M. (2003). Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrob Agents Chemother 47, Vikram, H. R., Havill, N. L., Koeth, L. M. & Boyce, J. M. (2005). Clinical progression of methicillin-resistant Staphylococcus aureus vertebral 379

5 A. Kirby and others osteomyelitis associated with reduced susceptibility to daptomycin. J Clin Microbiol 43, Voss, A., Mouton, J. W., van Elzakker, E. P., Hendrix, R. G., Goessens, W., Kluytmans, J. A., Krabbe, P. F., de Neeling, H. J., Sloos, J. H. & other authors (2007). A multi-center blinded study on the efficiency of phenotypic screening methods to detect glycopeptide intermediately susceptible Staphylococcus aureus (GISA) and heterogeneous GISA (h- GISA). AnnClinMicrobiolAntimicrob6, 9. Wootton, M., Howe, R. A., Hillman, R., Walsh, T. R., Bennett, P. M. & MacGowan, A. P. (2001). A modified population analysis profile method to detect Staphylococcus aureus with decreased susceptibilities to vancomycin in a UK hospital. J Antimicrob Chemother 47, Journal of Medical Microbiology 58